Regular readers will be quite familiar with the findings that cardiometabolic health appears to be far more related to “fitness” than to “fatness” – in other words, it is quite possible to mitigate the metabolic risks commonly associated with excess body fat by improving cardiorespiratory fitness.
Now, a study by Kathy Do and colleagues from York University, Toronto, published in BMC Obesity, shows that this relationship also holds for people with quite severe obesity.
The researcher studied 853 patients from the Wharton Medical Clinics in the Greater Toronto Area, who completed a clinical examination and maximal treadmill test. Patients were then categorized into fit and unfit based on age- and sex-categories and in terms of fatness based on BMI class.
Within the sample, 41% of participants with mild obesity (BMI<35) had high fitness whereas only 25% and 11% of the participants with moderate (BMI 35-40) and severe obesity (BMI>40), respectively, had high fitness.
Individuals with higher fitness tended to be younger and more likely to be female.
While overall fitness did not appear to be independently associated with most of the metabolic risk factors (except systolic blood pressure and triglycerides), the effect of fitness in patients with severe obesity was more pronounced. Thus, the prevalent relative risk for pre-clinical hypertension, hypertriglyceridemia and hypoalphalipoproteinemia and pre-diabetes was only elevated in the unfit moderate and severe obesity groups, and fitness groups were only significantly different in their relative risk for prevalent pre-clinical hypertension within the severe obesity group.
Similarly, high fitness was associated with smaller waist circumferences, with differences between high and low fitness being larger in those with severe obesity than with mild obesity.
Based on these findings, the researchers conclude that the favourable associations of having high fitness on health may be similar if not augmented in individuals with severe compared to mild obesity.
However, it is also apparent based on the rather low number of “fit” individuals in the severe obesity category (only about 1 in 10), that maintaining a high level of fitness proves to be more challenging the higher the BMI.
This week, the Lancet published the results of the SUSTAIN7 trial, an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries.
Eligible patients with type 2 diabetes (HbA1c 7·0–10·5% on metformin monotherapy, n=1201), were randomised to once-weekly injections of the GLP-1 analogues semaglutide 0·5 mg, dulaglutide 0·75 mg, semaglutide 1·0 mg, or dulaglutide 1·5 mg.
Over the 40 weeks of treatment, participants on semaglutide had a greater reduction in HbA1c than participants who were on corresponding doses of dulaglutide.
More interesting, in the context of this blog, semaglutide was also almost twice as effective in lowering mean body weight than dulaglutide.
Thus, bodyweight was reduced by 4·6 kg with semaglutide 0·5 mg compared with 2·3 kg with dulaglutide 0·75 mg and by 6·5 kg with semaglutide 1·0 mg compared with 3·0 kg with dulaglutide 1·5 mg.
As expected, the most frequent adverse effects were gastrointestinal.
Given that this was not actually a trial designed to maximise weight loss (as would have been attempted in a study primarily designed to study semaglutide as a treatment for obesity), these changes in body weight are certainly quite impressive.
These findings no doubt hold promise for the further development of semaglutide as an anti-obesity medication.
Disclaimer: I have received speaking and consulting honoraria from Novo Nordisk, the maker of semaglutide
Given the limited effectiveness of “lifestyle” interventions and the lack of access to medical treatments, many adolescents struggling with severe obesity are left with no option but to consider having bariatric surgery.
Now, a paper by Marc Michalsky and colleagues on behalf of the Teens LABS Consortium, in a paper published in Pediatrics, describes the effect of bariatric surgery on cardiovascular risk factors in adolescents undergoing these procedures.
The study includes 242 adolescents (76% girls, 72% white, mean age 17 ± 1.6 y, median BMI 51) undergoing bariatric surgery (Roux-en-Y gastric bypass (n = 161), vertical sleeve gastrectomy (n = 67), or adjustable gastric banding (n = 14)), at five centers.
At 3 years following surgery, weight was significantly lower in all groups (28%, 26%, and 8% for RYGB, VSG, and AGB, respectively).
Hypertension, observed in 44% of participants, declined to 15% at 3 years.
Dyslipidemia observed in 75% of participants, declining to 27% by 1 year and 29% by 3 years. This improvement was largely due to decrease in triclycerides and increases in HDL cholesterol.
Baseline diabetes was present in 13% of participants with major metabolic improvement (0.5%) by 3 years. Similarly, baseline impaired fasting glucose (26%) and hyperinsulinemia (74%) dramatically improved by year 3 (4% and 20%, respectively).
Improvements in these parameters were related to the degree of weight loss.
Remission rates were negatively correlated to higher age and positively correlated to female sex and white race.
Overall, the authors conclude that this study documents the improvements in cardiovascular risk factors in adolescent bariatric surgery.
Unfortunately, the study does not present any information on surgical complications or reoperation rates, an obvious matter of concern when it comes to surgery in this young population.
While there may well have been no alternative to surgical treatment in these kids, we can only hope that eventually medical treatments will become available for this population, hopefully with similar outcomes. Unfortunately, that may well still be a long way off.
Another series of articles in the 2018 JAMA special issue on obesity, deals with the impact of bariatric surgery on health outcomes and overall mortality.
The first article by Sayeed Ikramuddin and colleagues is an observational follow-up of a randomized clinical trial at 4 sites in the United States and Taiwan, involving 120 participants who had a hemoglobin A1c(HbA1c) level of 8.0% or higher and a BMI between 30.0 and 39.9. The study compared intensive lifestyle and medical management intervention based on the Diabetes Prevention Program and LookAHEAD trials for 2 years, with and without (60 participants each) Roux-en-Y gastric bypass surgery followed by observation to year 5.
At 5 years, 13 participants (23%) in the gastric bypass group and 2 (4%) in the lifestyle-intensive medical management group had achieved the composite triple end point (HbA1c less than 7.0%, LDL cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg).
In the fifth year, 31 patients (55%) in the gastric bypass group vs 8 (14%) in the lifestyle–medical management group achieved an HbA1c level of less than 7.0%.
As is to be expected, surgical treatment resulted in more serious adverse events (66 vs 38 events), most frequently involving gastrointestinal and surgical complications such as strictures, small bowel obstructions, and leaks.
A second study by Gunn Signe Jakobsen and colleagues from Norway, reports on changes in obesity related comorbidities in patients with severe obesity (BMI ≥40 or ≥35 and at least 1 comorbidity) undergoing bariatric surgery (n=932, 92 gastric bypass) or specialized medical (“lifestyle”) treatment (n=956) at a tertiary care outpatient center.
Based on drugs dispensed according to the Norwegian Prescription Database and data from the Norwegian Patient Registry and a local laboratory database, surgically treated patients had a greater likelihood of remission (RR, 2.1) and lesser likelihood for new onset of hypertension (RR, 0.4), a greater likelihood of diabetes remission (RR, 3.9) but also a greater risk of new-onset depression (RR, 1.5) and treatment with opioids (RR, 1.3.
Again, as expected, surgical patients had a greater risk for undergoing at least 1 additional gastrointestinal surgical procedure (RR, 2.0).
From these findings the researchers conclude that adding gastric bypass to lifestyle and intensive medical management alone in patients with severe obesity and type 2 diabetes, there remained a significantly better composite triple end point in the surgical group at 5 years.
The third study by Orna Reges and colleagues from Israel, was a retrospective cohort study in a large Israeli integrated health fund database, that compared 8,385 patients who underwent bariatric surgery compared to 25,155 nonsurgical patients matched on age, sex, BMI, and diabetes. The surgical interventions included laparoscopic banding [n = 3635], gastric bypass [n = 1388], and laparoscopic sleeve gastrectomy [n = 3362]
Over the approximately 4.5-year follow up period, there were 105 deaths (1.3%) among surgical patients compared to 583 deaths (2.3%) among nonsurgical patients.
Mortality rates were similar across the different types of surgery: [1.7%] who underwent laparoscopic banding, 18 [1.3%] gastric bypass, and 26 [0.8%] sleeve gastrectomy).
Form these findings the authors conclude that, compared with usual care, nonsurgical obesity management, was associated with lower all-cause mortality.
Finally, a fourth paper by Sarah Shubeck and colleagues from the University of Michigan, discuss the finding of a study by Anita Courcoulas and colleagues published in JAMA Surgery, which describes 7-year weight trajectories and health outcomes in the Longitudinal Assessment of Bariatric Surgery (LABS) Study that includes 1738 patients who underwent Roux-en-Y gastric bypass (RYGB) and 610 patients who underwent laparoscopic adjustable gastric banding (LAGB).
At 7 years, patients who had undergone RYGB lost 28% of initial weight with minimal weight regain between years 3 and 7 (3.9%) compared to patients who had undergone LAGB (14.9% weight loss with 1.4% regain).
Patients who had undergone RYGB benefitted from high rates of long-term relief from all 5 comorbidities evaluated (diabetes mellitus, high LDL cholesterol, high triglycerides, low HDL cholesterol level, and hypertension) at 7 years than those who had undergone LAGB.
Importantly, postprocedure mortality was very low with 3 deaths within 30 days of surgery and 7-year death rates of 3.7/700 person-years after RYGB (59 deaths) and 2.7/700 person-years after LAGB (15 deaths). Rates of operative revisions and reversals were low for patients in the RYGB group (0.92/700 person-years), but were significantly higher among patients in the LAGB group (30.29/700 person-years).
Taken together, all 4 studies document the considerable long-term health benefits associated with surgical treatment of severe obesity but also note that there are certain surgical risks (which vary between procedures) that need to be individually discussed with patients.
There is no reasonable argument against the fact that excess weight gain is one of the key drivers of diabetes risk, and it should come as no surprise to anyone, that losing weight (though bariatric surgery or otherwise) dramatically improves glycemic control in people living with type 2 diabetes.
So what exactly can we learn from the DIRECT study published by Michael Lean and colleagues in The Lancet?
For one, this is a large cluster-randomised trial of obesity intervention conducted entirely in a non-specialist primary care setting with significant weight loss (at least 15 Kg) and diabetes remission (defined as glycated haemoglobin (HbA1c) of less than 6·5% after at least 2 months off all antidiabetic medications) as the pre-defined primary outcome at 12 months.
In the intervention centres, a nurse or dietitian (as available locally) was given a total of 8 h structured training by the study research dietitians experienced in the Counterweight-Plus program.
Initial weight loss was induced with a total diet replacement phase using a low energy formula diet (825–853 kcal/day) for 3 months (extendable up to 5 months if wished by participant), followed by structured food reintroduction of 2–8 weeks (about 50% carbohydrate, 35% total fat, and 15% protein), and an ongoing structured programme with monthly visits for long-term weight loss maintenance.
Given the primary care non-specialist setting of this trial, the key findings (as summarized by the authors), were perhaps surprising:
“Just less than a quarter of participants in the intervention group achieved weight loss of 15 kg or more at 12 months, half maintained more than 10 kg loss, and almost half had remission of diabetes, off antidiabetic medication….Remission was closely related to the degree of weight loss maintained at 12 months, with achievement in 86% of participants with at least 15 kg weight loss, and 73% of those with weight loss of 10 kg or more. 28% of all eligible individuals volunteered to participate,17 and 79% completed the intensive total diet replacement phase…”
In general, the intervention was well tolerated with 117 out of 150 participants (78%) in the intervention group completing the intervention.
So here are the key learning from DIRECT:
For one, there should no longer be any doubt that “remission” of Type 2 diabetes is possible in a substantial number of patients, if we can help them achieve and sustain significant weight loss – the odds of experiencing remission are directly proportional to the amount of weight lost.
Secondly, using a strategy of low-calorie diets and behavioural intervention (allowing ample room for individual preferences) appears feasible in a primary care setting, delivered by health professionals with modest training in obesity management.
Obviously, as anyone who has seen weight loss before is well aware, the challenge in obesity management is more in keeping the weight off than in losing it in the first place. Although sustaining significant weight loss over 12 months is notable, one cannot but wonder how well the participants will do in keeping the weight off in the years to come. This is of course recognised by the researchers, who intend to follow the participants over the next 4 years.
Although a very low calorie diet may not be everyone’s cup of tea, given that the only other intervention that comes anywhere close to the results reported in this paper is bariatric surgery, the findings of this study are indeed notable.
Personally, I would assume that combining the dietary intervention presented in this study with additional pharmacological management may well prove sustainable in the long-term with benefits not just for diabetes control.
I say this because the complex biology of obesity dictates that individuals living with obesity will need a lot more than willpower and hope to sustain meaningful weight loss over time.